PROJECT SUMMARY The heterogeneous, multifactorial nature of Alzheimer's disease and the overlap of its temporal course with changes attributable to typical aging has been a critical barrier to the development of diagnostic tools and interventions targeting the direct effects of the disease on brain function and cognition. A major challenge is to understand how multiple age-related cascades combine in an individual to create vulnerabilities to cognitive decline during the progression of Alzheimer's disease. One prominent age-related cascade involves disruption of the dopaminergic system. While the dopamine system is not generally understood to be a direct contributor to Alzheimer's disease, patients with Alzheimer's disease exhibit impairments in the mesolimbic dopamine pathway and dopamine may play a role in the severity of neuropsychiatric and cognitive symptoms of Alzheimer's disease. This application proposes a disconnection model in which parallel pathways lead from neuropathological alterations to impaired brain network integrity and cognition. These parallel pathways are proposed to have direct and indirect points of interaction by which age-linked dopaminergic changes induce vulnerabilities to tauopathy and amyloidosis. That is, this is a ?dual hit? model where individuals with pre- existing age-related dopaminergic disruption are proposed to be more likely to exhibit declines in network integrity and cognition in the presence of tauopathy and amyloidosis. The overall goal is to test whether the pathways proposed by this model induce vulnerabilities during the progression of Alzheimer's disease. Each aim tests a different set of pathways in the model. First, the project tests an Alzheimer's disease cascade whereby tauopathy and amyloidosis impact integrity of a network known as the default network, leading to change in memory performance. Second, the project tests an age-related cascade whereby dopaminergic function impacts integrity of a frontoparietal control network, leading to change in executive function. Third, the project tests whether increased vulnerability to the Alzheimer's disease cascade is a function of network alterations from the age-related dopaminergic cascade. To test these aims, the project applies simultaneous magnetic resonance imaging and positron emission tomography data to acquire multiple measures of brain function and pathology. A sample of cognitively normal older adults and patients with mild cognitive impairment is tested and followed over time to cover the early spectrum of progression toward Alzheimer's disease. Successful completion will aid differential diagnosis, provide a model for vulnerability to Alzheimer's disease that could be extended to other age-related cascades, and provide alternative targets for bolstering neural integrity to delay or prevent vulnerability during the progression of early Alzheimer's disease.